2-halo-5-(substituted piperidino sulfonyl)benzoic acids

ABSTRACT

Certain mono- and disubstituted-5-sulfamylbenzoic acids, many of which are novel, and their use in lowering blood lipid levels in mammals.

United States Patent 1191 Holland Oct. 22, 1974 541 2-I- IALO:5-( SUI 3$IITUTED PIPERIDINO 260/470, 260/515 A, 260/516, 260/515 M, SULFONYL)BENZOIC ACIDS 260/518 R, 260/518 A, 2.60/519, 260/556 C [51] Int. ClC07d 29/34 [75] Inventorgm' Lyme [58] Field Of Search 260/293.73

[73] Assignee: Pfizer Inc., New York, 5 References Cited [22] Filed:Dec. 26, 1972 UNITED STATES PATENTS 21] APP] 318 213 3,444,177 5/1969Schmidt et a] 260/239.7 3,565,920 2/1971 Werner 2611/3472 Appl'camn DamFOREIGN PATENTS OR APPLICATIONS [63] Contml ation-m-part of Ser. No.206,5l4, Dec. 9,

1971, abandoned, which is a continuation-in-part of 729430 3/1969 Ser.No. 72,156, Sept. 14, 1970, abandoned.

Primary Examiner-Norma S. Milestone [52] US. Cl....-260/293.73, 260/239BA,260/239 BF, Assistant Examiner-S. D. Winters 2 60/2396, 260/239.65,260/239.7, 260/239.8, 260/247.1 R, 260/243 B, 260/247.2 R, 260/268 5,260/287 R, 260/293.72, 260/293.86, 260/293.9,

Attorney, Agent, or FirmC0nnolly and Hutz [5 7] ABSTRACT Certain monoanddisubstituted-S-sulfamylbenzoic acids, many of which are novel, andtheir use in lowering blood lipid levels in mammals.

14 Claims, No Drawings 1 Z-HALO-S-SUBSTITUTIJQ PrPERrnrn SULFONYL)BENZOIC ACIDS CROSS-REFERENCE TO RELATED APPLICATIONS This applicationis a continuation-in-part of copending application Ser. No. 206,514,filed Dec. 9, 1971, now abandoned which in turn is acontinuation-in-part of application Ser. No. 72,156 filed Sept. 14,1970, now abandoned.

BACKGROUND OF THE INVENTION Atherosclerosis, a form of arteriosclerosis,is characterized by accumulation of lipids in the aorta and in thecoronary, cerebral and peripheral arteries of the lower extremities. Asthese masses increase in size, the risk of thrombosis and occlusionarises.

. It has been found that those suffering from the dis ease exhibitelevated levels of plasma lipoprotein, of which cholesterol andtriglycerides comprise major constituents. While theetiology of thedisease is not yet fully understood, it is believed that B-lipoproteinsplay an important role, and it has been recommended that dietary habitswhich promote low ,B-lipoprotein plasma levels be observed. In addition,various therapeutic agents such as estrogens, thyroxine analogs andsitosterol preparations have been used to lower plasma cholesterollevels in individuals prone to the condition.

It has now been found that certain monoanddisubstituted-5-sulfamylbenzoic acids are effective in reducing plasmalipid levels. These compounds can be expected to be useful in thetreatment of atherosclerosis and related cardiovascular diseasesassociated with elevated lipid levels.

A number of 5-sulfamylbenzoic acids are found in the literature;

A S O 9 C O OH A B Reference N112 CI CHaNH Cl (C H3) 2N Cl 2 .5 H CI(CH3) (C2H5)N Cl 2 s 2 Cl i-C H NH Cl (CH3) (i-C3H1) N Cl NH2 Bl (C Ha)NH Br (C Ha) 2N B 1 (Cal-15) 2N B r 6H2(CH;)3N Br (CH3) NH NH2 (C2115)NH NH: 502115) 2N NH: CH3) (C2H5)N NH2 (i-CaH1) NH NH2 (CH) (i-CaH7)N NH(lH2 (CHrh-N NH? I (CH3) 2N CeHgNII (CIIQ)DN (i-C3H1) NH crrmN oimNH 1Jackman, at al., J. Pharm. PharmacoL, page 679 (1962). 2 Belgian Pat.620,741 1963). (Chem/111mm, 11350). K Kunzlo, at al., Hclvctica ChimicaActa, 52, 625 (1969).

U.S. Pat. 2,453,104 (1948), (Chem. Ahsln, 43, 7710).

In addition, 4-sulfamylbenzoic acids are found in the literature:

A Reference (C3H1) N (i-CsHmN (0 1%) 2N CB s HQNH 5 British Pat. 795,937(1958) (Chem. Alisha, 53, 297).

A series of sulfamylbenzoic acids with utility as uricosuric agents forrheumatism and arthritis are claimed in West German patent applicationDT No. 2,109,339. None of the 5-sulfamyl compounds of the presentinvention, however, demonstrated uricosuric activity when tested.

Although the foregoing summary has been disclosed by a diligent searchof the literature, it does not, of course, purport to be an exhaustivelisting of all known sulfamylbenzoic acids. Nevertheless, so far as canbe determined, the ability of the S-sulfamylbenzoic acids of the presentinvention to reduce plasma lipid levels has never before beenrecognized.

SUMMARY OF THE INVENTION It has been discovered that blood lipid levelsmay be reduced by administering to a hyperlipemic mammal a substanceselected from S-sulfamylbenzoic acids and the amides, lower alkyl estersand salts thereof with pharmacologically acceptable bases, saidsubstances being substituted in the 2-position by hydrogen, chloro,fluoro, bromo, hydroxy, methoxy, methylthio, amino, monoanddi-lower-alkyl amino, benzylamino, phene thylamino, piperidino, monoanddi-loweralkylpiperidino, pyrrolidino, hexamethyleneimino or morpholino,and in the 3-, 4- or 6-position by hydrogen, fluoro, chloro, bromo,methoxy, trifluoromethyl or methyl, with the proviso that if the2-substituent is hydrogen the substituent at the 3-, 4- or 6-position isselected from the group consisting of fluoro, chloro, bromo, methoxy,methyl and trifluoromethyl.

Also considered within the scope of the present invention are congenerswherein the 2-positional substituent is trifluoromethyl, lower alkoxy orlower alkyl.

The hypocholesteremic activity appears to be shared by all these monoanddisubstituted S-sulfamylbenzoic acids, but one would obviously avoid anysubstituents known to be toxic at a level required for lipid-loweringeffectiveness.

One preferred class of compounds of the aforementioned configuration isthat wherein the sulfamyl group is piperidinosulfonyl or substitutedpiperidinosulfonyl having up to two substituents each selected from thegroup consisting of alkyl, alkyloxy and alkyloxyalkyl of one to fourcarbon atoms in each alkyl group, hydroxy, chloro, bromo,trifluoromethyl, plhenyl, tolyl, benzyl, benzyloxy, benzyloxymethyl,chloromethyl and bydroxymethyl.

A second preferred class of compounds is that wherein the sulfamyl groupis RR"NSO wherein R and R' together with the nitrogen to which they areattached form a heterocyclic ring selected from the group consisting ofmorpholino, thiomorpholino, piperazinyl, hexamethyleneimino,heptamethylerieimino, octamethyleneimino, 3-azabicyclo[3, 2,2]nonanyl,tetrahydroisoquinolyl, tetrahydropyridyl and monoand disubstitutedderivatives of said heterocyclic rings said substituents being selectedfrom the group consisting of alkyl, alkyloxy and alkyloxyalkyl of one tofour carbon atoms in each alkyl group, hydroxy, chloro, bromo,trifluoromethyl, phenyl, tolyl, benzyl, benzyloxy, chloromethyl andhydroxymethyl.

'A third preferred class of compounds is that wherein the sulfamyl groupis wherein n has a value from O to 3;

A is selected from the group consisting of hydrogen, lower alkyl,cycloalkyl of to 8 carbon atoms, benzyl and phenyl; and

R and R are each selected from the group consisting of hydrogen, chloro,bromo, alkyl and alkoxy of from one to four carbon atoms, carboxy,trifluoromethyl, phenyl, benzyl and benzyloxy.

A fourth preferred class of compounds is that wherein the sulfamyl groupis RR NSO wherein R is hydrogen or lower alkyl and R is lower alkyl orcycloalkyl of 5 to 8 carbon atoms.

As discussed below, many of the substances of the aforementioned classesare novel, and as such form part of the present invention.

DETAILED DESCRIPTION OF THE INVENTION One subclass of novel andparticularly preferred compounds of the presentinvention embraces thoseof the formula:

COOH

wherein X is selected from the group consisting of fluoro, chloro,bromo, piperidino, monoand di-loweralkylpiperidino, hexamethyleneiminoand morpholino;

bromo, trifluoromethyl, phenyl, tolyl, benzyl,'benzyloxy,benzyloxymethyl, chloromethyl and hydroxymethyl.

Especially preferred are the compounds of the latter structure wherein Xis fluoro, chloro or bromo and R and R are each lower alkyl or benzyl.

A second and related subclass of novel and particularly preferredcompounds of the present invention embraces those of the formula:

COOII wherein U is selected from the group consisting of fluoro, chloro,bromo, di-lower-alkylamino, piperidino, monoanddi-lower-alkylpiperidino, morpholino, and hexamethyleneimino;

and R and R together with the nitrogen to which they are attached for aheterocyclic ring selected from the group consisting of morpholino,thiomorpholino, piperazinyl, hexamethyleneimino, heptamethyleneimino,octamethyleneimino, 3- azabicyclo[3,2,2]nonanyl, tetrahydroisoquinolyl,tetrahydropyridyl and monoand disubstituted derivatives of saidheterocyclic rings;

said substituents being selected from the group consisting of alkyl,alkyloxy and alkyloxyalkyl of one to four carbon atoms in each alkylgroup, hydroxy, chloro, bromo, trifluoromethyl, phenyl, tolyl, benzyl,benzyloxy, chloromethyl and hydroxymethyl.

A fourth subclass of novel and particularly preferred compounds of thepresent invention embraces those of the formula:

wherein n has a value of O to 3;

A is selected from the group consisting of lower alkyl, cycloalkyl offive to eight carbon atoms, benzyl and phenyl;

Z is fluoro, chloro or bromo; and

R and R are each selected from the group consisting of hydrogen, loweralkyl, chloro, bromo and phenyl.

A sixth subclass of novel and particularly preferred compounds of thepresent invention embraces those of 5 the formula:

wherein W is selected from the group consisting of fluoro, chloro,bromo, piperidino and monoand dilower-alkylpiperidino; R is hydrogen orlower alkyl; and R' is cycloalkyl of five to eight carbon atoms.

A seventh and closely related subclass of novel and particularlypreferred compounds of the present invention embraces those of theformula:

N-SO 00011 wherein R and R are each lower alkyl.

An eighth subclass of preferred compounds of the present invention arerepresented by the formula:

wherein n has a value ofO to 3 and R and R are each selected from thegroup consisting of hydrogen, methyl, chloro, bromo and phenyl; and Rand R" when considered together with the nitrogen to which they areattached form a heterocyclic ring selected from the group consisting ofmorpholino, piperidino, monoand dimethylpiperidino andhexamethyleneimino.

The sulfamylbenzoic acids of the present invention have been found to bewell tolerated in the form of the free carboxylic acid. If desired,however, they may be administered in the form of an amide, lower alkylester or salt of a pharmacologically acceptable base.

The amides include not only the unsubstituted amides but amides ofpharmacologically acceptable amines, for example, the amino acids, suchas glycine or 4-aminobutyric acid. The amides are readily prepared bystandard techniques, for example, by treating a correspondingsulfarnylbenzoic acid ester in alcohol with ammonia, or by combining thecorresponding sulfamyl benzoyl chloride with amine under basicconditions and precipitating the amide product with mineral acid.

Of the lower alkyl esters, the ethyl ester will generally be preferred.In addition, esters of complex alcohols such as acetamidoethyl alcoholmay be employed. The esters may be employed. The esters may be preparedby condensation of the acid with the corresponding alcohol in thepresence of acid catalyst.

The pharmacologically acceptable salts include the ammonium, sodium,potassium, calcium and magnesium salts, as well as salts withpharmacologically acceptable amines. The salts are prepared byconventional procedures, for example, by adding the acid to an aqueoussolution containing an equivalent amount of the appropriate base,followed by concentration to obtain the desired product. Although saltsformed from pharmacologically-unacceptable bases'are not usefultherapeutically, they may be used in the purification. For example, animpure acid can be purified by dissolving it in an aqueous solutioncontaining a pharmacologically unacceptable base and extracting theresulting salt solution with organic solvent to remove nonacidicimpurities. The free, purified acid is then isolated by acidifying theaqueous solution and filtering.

Although parenteral modes of administration of the compounds of thepresent invention may be employed, oral administration is effective andpreferred for its ob vious convenience. The products of the inventionare tested in vivo for hypolipemic activity in rats. Groups, eachcomprising four animals, of normal Sprague- Dawley (Charles River) malerats weighing from 160 to 220 grams are fed rat chow containing thecompound under test for two overnight feeding periods. On the morning ofthe third day the animals are anesthetized and bled from the abdominalaorta. The total plasma cholesterol is then determined by the method ofJ. J. Carr and l. J. Drekter, reported in Clin. Chem, 2, 353 (1956).Most of the tests are conducted at a feed concentration of 0.15 to 0.25weight percent of the compound under test, but lower levels, 0.01 to0.10 weight percent, are employed in some instances where particularlyhigh potency is anticipated. The plasma cholesterol level of the treatedanimals is found to be significantly reduced when compared to animalsnot receiving the test compound.

This pharmacological test for measuring hypocholesteremic activity is areasonably reliable indication that similar activity in humals can beexpected. In fact, those compounds effective in the rat which have beentested in humans have demonstrated similar activity.p-Chlorophenoxyisobutyric acid, ethyl ester, marketed as Atromid'S. awell-known and clinically effective hypocholesteremic agent, causes a30-35 percent choles-' terol fall in the rat test when administered at alevel of 0.25 percent in the feed.

In humans, an individual having a plasma cholesterol level above 260 mg.percent (mg. per ml.) or a plasma triglyceride level about mg. percentis regarded as hyperlipemic. The term lipids is used herein in the broadsense to include triglycerides, cholesterol, phospholipids and freefatty acids. Plasma lipids are carried in the body in the form oflipoproteins, i.e., protein complexes. These may be separated byelectrophoresis into several fractions: high density or a-lipoprotein,containing a high proportion of phospholipids; low-density orB-lipoprotein, containing a major proportion of cholesterol; verylow-density or pre-B-lipoprotein; and chylomicrons; the latter twofractions containing a major proportion of triglycerides. In aparticular individual, one of the four fractions may be elevated. Theagents of the present invention depress plasma lipoprotein, withassociated cholesterol and triglyceride, and hence are expected to be ofvalue of hyperlipoproteinemic individuals.

One of the novel compounds of the present invention,2-chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)- benzoic acid, whichexhibits higher potency than Atromid-S in the rat test, has producedsignificant depression in plasma cholesterol and triglycerides in humanstudies. Overall reductions compare closely with those produced byAtromid-S in similar populations. In these clinical studies, thecompound was administered in three equally divided doses at daily levelsof 0.5-1.5 grams. It is now being further evaluated in hyperlipemichumans in the form of capsules containing 250 mg. of active ingredient,at a dosage schedule of two capsules three times daily. Further testingat a level of one capsule three times daily, equivalent to 0.75 gram perday, is also planned.

Among those compounds of the preferred classes, 2-chloro--(cis-3,5-dimethethylpiperidinosulfonyl)benzoic acid,2,3-dichloro-5-(cis-3,S-dimethylpiperidinosulfonyl)benzoic acid,2-chloro-5-(N-ethyl- N-[ Z-p-chlorophenethyl -aminosulfonyl )benzoicacid and 2,3-dichloro-5-(N-ethyl-N-[2-p-chlorophenethyl]-aminosulfonybbenzoic acid are particularly outstanding.

Obviously, the optimum dosage level for a particular compound of thepresent invention will vary with the relative potency of the substanceand with the age, weight and response of the particular patient. Anapproximation of suitable dosage levels for various compounds can beestimated from their potency in the rat test relative to a standardwhich has been tested in humans, such as Atromid-S or2-chloro-5-(cis-3,5- dimethylpiperidinosulfonyl)benzoic acid. Indetermining relative potency, dose response curves are preferablyconstructed by rat testing at several dosage levels, for example, atseven levels. A compound which proves twice as potent as the standard inthis test will generally be evaluated in toxicology as a candidate foruse at half the level employed with the standard.

Having full regard for the foregoing factors, it is considered that aneffective daily dosage of the compounds of the present invention inhumans will generally range from about 0.3 to 3 grams per day, in singleor divided dosage, or at about 5 to 50 mg. per kg. of body weight. Thesevalues are illustrative, and there may, of course, be individual caseswhere higher or lower dosage ranges are merited.

The sulfamylbenzoic acids of this invention can be administered eitheralone, or preferably, in combination with a pharmaceutically-acceptablecarrier. They may be combined with various pharmaceuticallyacceptable,inert carriers in the form of tablets, capsules, lozenges, troches,powders, aqueous suspensions or solutions, elixirs, syrups and the like.Suitable carriers include solid diluents or aqueous media and nontoxicorganic solvents. The oral pharmaceutical compositions of this inventionmay be suitably sweetened and flavored by means of various agentscommonly employed for such a purpose.

For parenteral administration, solutions or suspensions of the hereindescribed sulfamylbenzoic acids in sesame or peanut oil or in aqueouspropylene glycol solutions can be employed, as well as sterile aqueoussolutions of the corresponding water-soluble salts. Such solutions aresuitable for intramuscular and subcutaneous administration. Sterileaqueous solutions are additionally useful for intravenous injection,provided that their pH is suitably adjusted and buffered, if necessary,and the liquid diluent rendered isotonic with saline or glucose.

The herein disclosed compounds may also be useful in other aspects ofabnormal metabolism, the latter possibly accounting for clinicalproblems in diabetes, pancreatitis, coronary heart disease, andcerebrovascular disease. Hence the ability of sulfamylbenzoic acids ofthis invention to regulate lipid metabolism might find utility in thetreatment of said diseases.

The compounds of the invention are readily prepared by reactions wellknown to those skilled in the art, as summarized in the reaction schemesof Charts 1 and 2, wherein I ll represents chlorosulfonation of a 2-substituted benzoic acid, where X is fluoro, chloro, bromo or methyl andT is hydrogen, fluoro, chloro, bromo, trifluoromethyl, methoxy ormethyl;

ll lll represents reaction of a 2-substituted-5- chlorosulfonyl benzoicacid with amine in the presence of alkali or in a non-aqueous mediumsuch as methylene chloride;

lll IV represents replacement of a 2-halo substituentby a 2-amino group,effected by refluxing the sulfamylbenzoic acid with the correspondingamine;

lll V represents replacement of a 2-halo substituent by a 2-alkoxygroup, effected by heating the sulfamylbenzoic acid with thecorresponding alcohol in the presence of sodium hydride;

lll Vl represents replacement of a 2-halo substituent by a methylthiogroup, effected by heating the sulfamylbenzoic acid with sodium orpotassium salt of methylmercaptan;

' Ill Vll represents replacement of a 2-halo substituent by a 2-hydroxygroup, effected by heating the sulfamylbenzoic acid in the presence ofstrong alkali such as sodium hydroxide or potassium hydroxide;

[X X represents chlorosulfonation of a substituted benzoic acid, where Tis a substituent at the 3- or 4-position selected from the groupconsisting of fluoro, chloro, bromo, trifluoromethyl, methyl andmethoxy;

X Xl represents reaction of a substituted-5- chlorosulfonylbenzoic acidwith an amine in the presence of alkali or in a non-aqueous medium suchas methylene chloride;

Xll Xlll represents a series of reactions converting a5-nitro-6-substituted benzoic acid (or lower alkyl ester) where T isfluoro, chloro, bromo, methyl, meth- ,oxy or trifiuoromethyl to thecorresponding 5-sulfamyl- 6-substituted benzoic acid via reduction ofthe nitro group employing stannous chloride followed by diazotization ofthe amino moiety and reaction of the resulting diazonium salt withsulphur dioxide to form the sulfonyl chloride, which is subsequentlyreacted with an appropriate amine in the presence of alkali or in a nonaqueous medium such as methylene chloride; and

XIV XV represents N-alkylation ofa substituted- S-phenylor-phenylalkyl-aminosulfonyl benzoic acid, e.g., by treatment with thecorresponding alkyl or am!- Chart 1 COOH (3180311 OlSOz- 00011 l RQNHR2NSO COOH RENH R2NSO2- C0011 IV III RENSOT" COOH R2NSO. COOH I NaOH ORSCH: T T

V VI l RzNSO COOH VII Chart 2 COzH CHSOSH OlOzS -COzH IX X RQNOzSfi-CWHT Q XI Chart 3 OzN 00211 [H] HzN-- COzH' HNO2 XII T T l 1 C180; COgHRZNH RZNSOZ 0 11 XIII H -(CIIa) nNSO C O OH Xly T Rio COOII Therequisite starting materials leading to the products of the presentinvention are commercial reagents, or are compounds whose syntheses areeither described previously in the chemical literature or are preparedby chemical reactions well known to those skilled in the art.

EXAMPLE 1 2Chloro-5-chlorosulfonylbenzoic Acid A mixture ofo-chlorobenzoic acid (2.0 kg.) and chlorosulfonic acid (10.5 kg.) isheated at l00 C. for 5 hours. The reaction mixture: is cooled to 25 C.and then slowly poured into a 10 liter mixture of ice and water. Theaddition requires about 1 hour, and the temperature is maintained below10 C. during this pe riod by the addition of more ice. The final volumeof slurry after the quench is about 40 liters. The solid material iscollected and thoroughly washed on the funnel with fresh water. Thecrude wet cake is dissolved in 16 liters of diethyl ether. The etherlayer is washed once with 2 liters of saturated aqueous sodium chloridesolution and then dried over anhydrous magnesium sulfate. The filteredether solution is concentrated in vacuo with the continual addition ofhexane. The resulting hexane slurry is concentrated to a final volume ofapproximately 8 liters and filtered. The crystalline cake is washed withhexane and dried in the atmosphere to give 2.5 kg. of product (76.8% oftheory), m.p. l49l 5 1 C.

cis-3,S-Dimethylpiperidine Hydrochloride 3,5-Lutidine (6,475.0 g.) ishydrogenated under 1,000 psi hydrogen pressure in ethanol using 1,665 g.of 5% rhodium on carbon catalyst (50% H O) at room temperature. Thecatalyst is filtered off and anhydrous hydrogen chloride bubbled intothe filtrate at a temperature below 40 C. until the solution is stronglyacidic. The solution is then concentrated in vacuo to a thick slurrywhich is diluted with 40 liters of hexane. The crystalline material isfiltered off and dried in the atmosphere to give 8.9 kg. of crudeproduct. The crude 3,5- dimethylpiperidine hydrochloride is dissolved in14 liters of water and the pH of this solution adjusted to 7.0 withdilute sodium hydroxide solution. The mixture is washed with 7 l. andthen with 3 l. of chloroform to remove unreduced 3,5-lutidine. Theaqueous solution is then adjustedto pH 12-13 by the addition of 40percent sodium hydroxide solution and extracted with 6 l. and then with3 l. of chloroform. The combined chloroform extract is dried overanhydrous magnesium sulfate and chilled at 5 C. in an ice bath.Anhydrous hydrogen chloride is then injected until the solution isstrongly acidic. The chloroform solution is concentrated in vacuo asbenzene is continuously added. When most of the chloroform has beenreplaced, the product is filtered from about 36 l. of benzene. Thefilter cake is washed with cold benzene and hexane, and air dried, toobtain 4.8 kg. of product, m.p. 222-224 C.

2-Chloro-5-(cis-3,S-dimethylpiperidinosulfonyl)benzoic Acid2-Ch]oro-5-chlorosulfonylbenzoic acid (510.2 g.)

. ried in 7.0 l. of water and stirred at 15 C. as a cold soabout 3 l.and the crystalline material filtered off. The

filter cakeis washed with isopropyl alcohol and ether. Air drying gives471.0 g. of crystalline product, m.p. 250-25 1 C.

Anal. Calcd for C H,,,0,NSC1: C, 50.67; H, 5.47; N, 4.22.

Found: C, 50.73; H, 5.46; N, 4.24.

In the same way, 2-chloro-4-(cis-3,S-dimethyli di w t w? id P 91213???9. i

.12 EXAMPLE 4 2-Ch1oro-5-(4-Chloropiperidinosulfonyl)benzoic Acidfluxing 4-hydroxypiperidine hydrochloride, 4.2 g., with 20 ml. thionylchloride for minutes, and evaporating to dryness.

10 m moles of this product is permitted to react with 10 m moles of2-chloro-5-ch1orosu1fonyl benzoic acid as described in the previousexample. After washing with ether and acidifying, the reaction mixtureis extracted with ethyl acetate and the extract is evaporated todryness. The residue is then dissolved in a mixture of 3 ml. acetone and10 ml. ethyl acetate and passed over 30 grams silica gel packed in acolumn in a solution of 5 percent acetic acid in 1:1 benzenezhexane. Thecolumn is eluted with the same solvent mixture and the product isolatedby evaporation of first effluent fractions. The residue is purified bydissolving in ml. acetone, adding an equal volume of hexane, anddecanting the supernatant from the resulting precipitate. Thesupernatant is then concentrated to half volume to crystallize 0.45 gramof product, m p. l93-195 Anal. Calc'd for c,,H,,o,Nsc|, Mw 338.2): c, 4

2.62; H, 3.87; N, 4.14. Found: C, 42.79; H, 3.99; N, 3.91.

prepared from 2-chloro-4-chlorosulfonylbenzoic acid.

EXAMPLE 2 2-Chloro-5-(trans-dl-3,5-dimethylpiperidinosulfonyl)- benzoicAcid The mother liquors of the reduced 3,5-lutidine of Example areevaporated to dryness. The residue contains approximately 78 percenttrans and 22 percent cis isomers. A portion of this material is reactedwith 2- ch1oro-5-chlorosulfonylbenzoic acid by the method of Example 1.Recrystallization from methylene chloride replaced with benzene yieldsthe desired product, m.p. 188-191.5 C.

EXAMPLE 3 EXAMPLE 5 2-Ch1oro-5-( 2-[ p-chlorophenyl]ethylaminosu1fonyl)-benzoic Acid 2-Ch1oro-5-ch1orosu1fonyl benzoic acid, 3.5 g. (0.014mole), is added to a solution of 2-(p-ch1orophenyl)ethy1amine, 6.5 g.(0.042 mole) in 25 ml. methylene chloride. The resulting slurry isstirred overnight and filtered to recover 9.7 g. of residue. This isrecrystallized three times from aqueous isopropanol, then dissolved inIN aqueous sodium hydroxide, washed three times with ether, and thenacidified with cone. hydrochloric acid. The resulting precipitate isrecrystallized twice from aqueous isopropanol to yield the desiredproduct, m.p. l76-178 C.

Anal. Calc'd for C H O NSC1 :C, 48.14; H, 3.50; N, 3.72. Found: C,48.19; H, 3.31; N. 3.42.

EXAMPLE 6 2-Ch1oro-5-chlorosulfonylbenzoic acid is reacted by themethodof Example 1 with each of the indicated amines to yield thecorresponding sulfamylbenzoic acid.

Anal. Calcd for c,,H,,o,Nsci, (MW 360.65): c. 36

.64; H, 3.35; Found: C, 36.66; H, 3.39;

Amine Product, m.p. (C.)

3 peridylcarbinol 3,5

2,2 2-benzylpiperidine 4-e 3-h 3 5 -diethylpiperidine-dimethylthiomorpholine ydroxypiperidine is-3,4-dibenzyloxypyrrolidine-dipropylpiperidine ,S-dimethylpiperidinc ,5-dimethy1morpholinethoxy-4-pheny1piperidine Amine 3,4-dihydroxypiperidinel-[N-flhydroxyethyl-4-piperidylI-3-[4-piperidy1lpropane4-benzyloxymethylpiperidine 3-methoxypi eridine l-octamethy eneiminedimethylamine 17% aq. ammonia 3-benzylplperidinc 3,5-dibenzylpiperidine3.4-dich1oropiperidine 1.2.3.4-tetrahyd roisoquinoline EXAMPLE 72-Bromo-5-(Z-methylpiperidinosulfonyl)benzoic Acid2-Bromo-5-chlor0su1fonylbenzoic acid is prepared by reactingo-bromobenzoic acid with chlorosulfonic acid by the method of Example 1.This is reacted with 2-methylpiperidine by the procedure of Example 6.Recrystallization from acetone-hexane yields the product, m.p. l48f-l50C. Q

Product, mp. (C.)

Anal. Calcd for C H QNSBr (MW 362.2): Found: C,

EXAMPLE 8 The method of Example 2 is repeated with 2-bromo-S-chlorosulfonylbenzoic acid in place of 2-chloro-5-chlorosulfonylbenzoic acid to yield -bromo-5-( trans-d1-3,5-dimethylpiperidinosulfonly benzoic acid, m.p. l88-l90C.

EXAMPLE 9 The following compounds are prepared by reacting2-brorno-5-ch1orosu1fonylbenzoic acid with the appropriate amine by themethod of Example 7:

Compound 2-bromo-5-(cis-3,S-dimeth lpiperidinosulfonyl)benzoic acid2-bromo-5-(3-trifluoromet y1-4-chlorophenylsulfamyl)benzoic acid2-bromo-5-(3-phenylpropylsu1famyl)benzoic acidZ-brommS-M-m-tolyl-1-piperazinylsu1fony1)benzoic acid2-bromo-5-(2-carboxyphenylsulfamyl)benzoic acid2-bromo-5-(N-phenyl-N-butylsulfamyl)benzoic acid2-bromo-5-(4-mcthoxybenzyl)sulfamylbenzoic acid 2-bromo-5-(4-phenylpieridinosulfonyhbenzoic acid 2-bromo-5-(3-azabicyco[3,2,2]nonan-3-ylsu1fony1)benzoic acid 2-bromo-5-( 1,2,5,6-tetrahydro-1-pyridylsulfonyl)benzoic2-bromo-5-(3,5-dielhylpiperidinosulfonyl)benzoic acidZ-bromo-S-(3-benzylpiperidinosulfonyl)benzoic acid2-bromo-5-(3.5-dibenzylpiperidinosulfonyl)benzoic acid2-bromo-5-(2-lp-chlorophenyllethylaminosulfonyl)benzoic acid pressure toremove the ethanol, diluted with water, and washed twice with diethylether. The reaction mixture is then acidified with concentratedhydrochloric acid and the oil which separates is extracted three timeswith diethyl ether. The combined extract is dried, concentrated, treatedwith hexane and filtered to recover 3.7 grams of solid product.

The product is purified by recrystallization from isopropyl etherhexaneand chromatography in benzene on ml. of silica gel in a column. Thecolumn is eluted with 5% acetic acid in 1:1 benzenezhexane and theeffluent eyaporated at reduced pressure to obtain 2.7

M.P. (C.)

EXAMPLE 1O 2-Bromo-5-(N-propyl-N-Z-[p-chlorophenyl1e-' thylaminosulfonylbenzoic acid grams, m.p. 125-l28 C. Recrystallization from diethyl etherreplaced with hexane raises the melting point to 128-l29 C.

i covered.

Anal. Calc'd for C H O NSBrCI (MW 461): c, 46.92; H, 4.16; N, 3.04.Found: c, 47.1 1; H, 4.13; N, 2.88.

EXAMPLE 11 3.3 Grams of white crystalline product, m.p.

l22-123 C. is obtained. I

Anal. Calc'd for C H QNSBrCI: C, 44.40; H, 3.49; N 3.24; Found: C,44.11; H, 3 42; N, 3.18.

EXAMPLE 1 2 i v 20 2-Bromo-5-(N-benzyl-N-2-[p-chloropheny1]-ethylaminosulfonyl)benzoic Acid T rqs y t sersp r' by h pr s ur pffiaamr3-Benzyloxypiperidine.

1Acetyl-3-benzyloxypiperidine (0.043 mole), sodium hydroxide (0.086mole) and water (30 ml.) are combined and refluxed for 24 hours. Thereaction mixture is saturated with potassium carbonate and extractedthree times with ether. The ether is removed by evaporation and theyellow oil is distilled at 92-94 C. (0.3 mm Hg.).

2-Bro mo-5-( 3 -benzyloxypiperidinosulfonyl)benaoic Acid2-Bromo-5-chlorosu1fonylbenzoic acid is reacted with3-benzyloxypiperidine by the method of Example 1. Recrystallization fromether-hexane yields the prod uct, m.p. l77- 178? C.

Anal. Calc'd for C,,,H, O NSBr (MW 454): C, 50

22; H, 4.44; N, 3.03. 51; H, 4.52; N, 3.41.

Found: c, 50.

2-Chloro-5-( 3-benzyloxypiperidinosulfonyl)benzoic Acid.

Anal. Calcd for C H O NClBr (M 3.7 l I Found: C, 3

EXAMPLE l3 l-Acetyl-3-hydroxypiperidine 3-Hydroxypiperidine (0.4 mole)is dissolved in 150 ml. of methylene chloride. The solution is cooled toC. and acetic anhydride (0.46 mole) is added dropwise, maintaining thetemperature under C. The reaction mixture is allowed to come to roomtemperature, and is then refluxed for 2 hours. The methylene chloride isevaporated off, and the remaining liquid is distilled under high vacuum.A thick yellow oil is collected at l22-126 C. (0.3 mm Hg).

1-Acetyl-3-benzy1oxypiperidine 1-Acetyl-3-hydroxypiperidine (0.10 mole)is dissolved in 50 ml. of dimethylformamide. 0.12 Mole of sodium hydride(56%) is added over a 10 minute period, and the reaction mixture isstirred for minutes. Benzyl chloride (0.12 mole) is added dropwise overa 30 minute period, and the reaction mixture is then heated on a steambath for 30 minutes. Water (3volumes) is added, the solution extractedwith ether, the ether extract washed with water and the ether removed byevaporation. A yellow oil is obtained on distillation at l36l40 C. (0.01mm Hg.).

Anal. Calcd for C H O N: C. 72.07; Found: C. 72.18;

H, 8.21; N, 6.00. H, 8.25; N, 5.98.

with 3-benzyloxypiperidine by the method of Example 1. Recrystallizationfrom ether-hexane yields the product, m.p. 173-l74 C.

Anal. Culcd for C,,,H,,,0,,NSC1: C, 55.67; H, 4.92; Found: C, 55.93; H,5.09;

EXAMPLE 14 (4-phenyl-1-piperizinosu1fonyl)benzoic acid; 2-fluoro--phenylaminosulfonylbenzoic acid; 2-f1uoro-5-(3,4-dichlorobenzylaminosulfonyl)benzoic acid; 2-f1uoro-5--methyl-N-[Z-p-chldrophenethyl]aminosu1fony1)benzoic acid;2-fluoro-5-(N-benzyl- N-[3,5-dimethy1benzy1]aminosulfony1)benzoic acid;2-fluoro-5-cyclohexylaminosulfonylbenzoic acid; 2-fluoro-5-(N-ethyl-N-cycloheptylaminosulfonyl)benzoic acid; and2-fluoro-5-cyclooctylaminosulfonylbenzoic acid.

EXAMPLE 2-N,N-diethylamino-5-( 3,S-dimethylpiperidinosulfonyl )benzoicAcid o-Fluorobenzoic acid is reacted with chlorosulfonic acid by themethod of Example I to form 2-fluoro-5- chlorosulfonylbenzoic acid. Thisis reacted with 3,5- dimethylpiperidine by the method of Example 1 toform 2-fluoro- 5-(3,5-dimethy1piperidinosulfonyl)benzoic acid. Thisproduct (0.0015 mole) is heated to 60 C. with diethylamine (10 m1.) andethanol (3.0 ml.) to form a clear solution, and the reaction mixture isthen heated at reflux temperature for 24 hours. The resulting brownsolid is filtered off, dissolved in IN NaOl-l, washed twice with ether,and the product precipitated by the addition of concentrated HCl.Recrystallization from diethyl ether replaced by isopropyl ether yieldsthe product, m.p. 139.5-140 C.

Anal. Calcd for C H O N,S: C. 58.67;

Found: C. 58.67

EXAMPLE 16 The following compounds are prepared by the method of Example15.

Compound 18 EXAMPLE 17 2-Amino-5-(3,5-dimethy1piperidinosulfonyl)benzoicAcid 2-F1uoro-5-(3,S-dimethylpipericlinosulfonyl)benzoic acid iscombined with 10 ml. of benzylamine and heated at 1 10 C for 15 minutes.The reaction mixture is concentrated in vacuo (10 mm. Hg.) at 85 C. to athick oil. After the addition of '75 m1. of water, 2-

" benzy1amino-5-( 3 ,S-dimethylpiperidinosulfonyl )benzoic acid,- m.p.220-227 C., is precipitated by the addition of concentrated hydrochloricacid.

1.9 Grams is dissolved in ml. of acetic acid, and hydrogenated in thepresence of 2.00 mg. of palladium on carbon on a Parr shaker overnightat C. The filtered solution is concentrated to dryness, taken up in 40m1. of isopropyl alcohol, and allowed to crystallize from 10 ml. ofsolution. Recrystallization from isopropyl alcohol yields the product,m.p. 240-24l C.

Anal. Culc'd for C H O N S: C. 53.82; H.

Found: C, 53.78; H

EXAMPLE l8 M.P. (C.)

2-(B-rnethylpiperidino)-5-piperidinosulfonylbenzoic acid2-pyrrolidiny1-5-(3.5-dimethylpiperidinosulfonyl)benzoic acid2-piperidino-5-( Z-[p-chlorophenyl lethylaminosu1fony1)benzoic acid . 1920 tracted with ether, and the ether extract washed with minutes withml. of acetone and 2 ml. of water. The water and evaporated to an oil.The oil crystallizes from clear solution is evaporated to dryness. Theresidue is isopropyl ether-hexane. Recrystallization from the dissolvedin hot methanol, and the 2- same solvent mixture affords the product,m.p. oxopiperidinosulfonyl product, m.p. 207.5-209.0 C., 102l04 C. 5 isobtained by addition of ether-hexane.

Anal. Calcd for CMHHOQNS (MW 341.4): C, 56.29; H, 6.79; N, 4.10. Found:C, 56.13; H, 6.65; N, 3.66.

Anal. Calcd for C,2H,,O -,NSC1 (MW 317.75): C, 45.36; H, 3.81; N, 4.41.Found: c, 45.30; H, 3.83; N, 4.35.

. EXAMPLE 19 l5 1 EXAMPLE 21 z-Hydroxyjll3 methygggrldmosulfonyubenzolc2-Ch1oro-5-(4-hydroxymethylpiperidinosulfonyl)benzoic Acid2-F1uoro-5-(3-methylpiperidinosulfonyl)benzoic a acid (5 millimoles) and25 ml. of 1N aqueous sodium 2-Ch1oro-5-chlorosulfonylbenzoic acid (5.0g.) is

hydroxide are heated overnight on a steam bath. The added to a solutionof 4-piperidy1 carbinol (6.9 g.) in precipitate obtained onacidification of the'alkaline So- 40 ml. of methylene chloride. Thesolution is refluxed lution is redissolved in 2.5N sodium hydroxide andfor 2 hours, cooled to room temperature and stirred heating is continuedon the steam bath for 3 /2 hours to overnight. The solution isevaporated to dryness, the complete the reaction. Acidification withconcentrated gummy residue dissolved in lN sodium hydroxide, andHClyield's the crystalline product, m.p. l89190 C., the alkalinesolution extracted twice with ether. The which is purified byrecrystallization from acetoneaqueous solution is acidified withconcentrated hydrohexane. H Y v chloric acid, and the precipitaterecovered by. filtration.

2.17',1-1, 5.73; N, 4.68. Found: 2.19; H 5 75; N 4.52.

EXAMPLE 2O 'i Recrystallization from ethyl acetate yields crystals, Ym.p. l85l87 C. 1 .-C '(zoxoplpendmosulfonyl)benzolc Acld In the sameway, the following products are prepared fi-Amino-n-valeric acid (0.03mole) is dissolved in 50 from the corresponding piperidyl carbinols:

M.P. c.)

2-chloro-5-(2-hydroxymethylpiperidinosulfonyl)benzoic acid 136-1382-chloro-5-(3-hydroxymethylpiperidinosulfonyl)benzoic acid 191-193 ml.of water and 3O ml. of 1N aqueous sodium hydroxi 1 EXAMPLE 22 ide. Tothis solution is added 2-chloro- 5-chlorosulfonylbenzoic acid (0.03mole) followed by 2'Chlr'5'(4'chlorom?thylPlpendmosulfonyl)ben' 25 m1.of 2.5N sodium hydroxide. After stirring at room Zolc temperature forabout 25 minutes, the solution is acidi- 2 -Chl r-5-(4-hydroxymethylpiperidinosulfonyl)- fied with concentratedhydrochloric-acid. The precipibenzoic acid (5.0 g.) is refluxedovernightwith 50 ml. tated 2-chloro-5-(4-carboxybutylsulfamyl)benzoic of thionylchloride. After evaporation to dryness, the acid, on recrystallizationfrom acetone-ethyl acetate, residue is dissolved in ml. of acetone, 30ml. of melts at 173-175 C. water added and the mixture is allowed tostand at Anal. Calcd for C,,H,,0,,NSC1 (MW 335.8): C, 42.92; H, 4.20; N,4.17. I Found: C, 43.06; H, 4.23; N, 3.90.

2-Chloro-5-(4acarboxybutyl)sulfamylbenzoic acid 60 room temperature fora half hour The solution is then (0.5 g.) is refluxed for 2 hours with10 m1. of thionyl filtered and concentrated to half volume. On theaddichloride, and then evaporated to dryness to obtain 2- tion of 20 ml.of water a precipitated oil is obtainedchloro-5-(4-chloroformylbutylsulfamyl)benzoic acid. which crystallizeson stirring. Recrystallization from 0.4 Gram is stirred at roomtemperature for about 15 acetone-benzene yields the product, m.p.175-1'77 C.

Anal. Calcd for C H O NSC1 (MW 352.23): C,

' 21 1n the same way, the following chloroinethyl compounds are preparedfrom the products of the previous example:

(0.5 ml. Dimethyl sulfate and NaOH are added during the course of thereaction to maintain basicity. After cooling to room temperature, thereaction mixture is MP. (C.)

2-chloro-5-(2-chloromethylpiperidinosulfonyl)benzoic acid2-chloro-5-(3chloromethylpiperidinosulfonyl)benzoic acid I EXAMPLE 232-Chloro-5-( l,2,5,6-tetrahydropyridylsulfonyl )benzoic Acid V2-Chloro-5-chlorosulfonylbenzoic acid (25.5 g.) is added in smallportions over-a 5 minute period with cooling to a solution ofl,2,5,6-tetrahydropyridine (25.0 g.) in 200 ml. of water. After stirringat room temperature for a half hour, the reaction mixture is acidifiedwith concentrated hydrochloric acid. The

crystalline precipitate is filtered off and dissolved in 75 ml. ofmethylene chloride and ml. of ether. .After concentration to 50 ml.,hexane is added to turbidity, affording crystals, m.p. 180-182 C. I

2-Chloro-5-( 3 ,4-dibromopiperidinosulfonyl )benzoic 1 Acid 2-Chloro-5-(1 ,2,5 ,6-tetrahydropyridylsulfonyl)ben zoic acid (2.0 g.) isdissolvedin ml. of hot acetic acid. Bromine (3.0 ml.) is added dropwise whileheating the acetic acid solution for 2 hours at 100 C. The solution istaken to dryness in vacuo. The residue is dis- Anal. Calcd for C,',H, 0NSCl (MW.349.8): C, 44.63: H, 4.61; N, 4.04 Found: c. 44.14; H, 4.66; N,3.74

EXAMPLE 25 2-Chloro-5-(4-methylenepiperidinosulfonyl)benzoic 25 Acid2-Chloro-5-(4-chloromethylpiperidinosulfonyl)ben-' zoic acid (0.5 g.) isdissolved in 10 ml. of 5N sodium hydroxide and refluxed for one hour."10 ml. of water is then added and the mixture is acidified withconcentrated hydrochloric acid. The precipitated solid ischromatographed on a 10 g. silica gel column with a developing solventsystem of 1:7 benzenezhexane containing 5% acetic acid. 2-Chloro-5-(4-methylenepiperidinosulfonyl)benzoic acid, m.p. .157-160 C., is isolatedfrom the first fraction.

solved in 20 mlfof 1N sodium hydroxide and then acidified withconcentrated hydrochloric acid. The precipitated gum is dissolved inether, which is then washed Anal. Calc'd for C H O,NSCl (MW 316): C,49.44; H, 4.47; N, 4. Found: C, 49.71; H, 4.44; N, 4.

In the same way, the following compounds are prepared from thecorresponding 5-chloromethylpiperidinosulfonyl benzoic acids:

M.P.(C.)

2-chloro-5-(3-methylenepiperidinosulfonyl)benzoic acid -171 158-1632-bromo-5-(3-mcthylenepiperidinosulfonyl)benzoic acid with water. Theproduct crystallizes as the ether is replaced with benzene on a steambath. Recrystallization from acetone-benzene yields the purifiedproduct, m.p. l76178 C.

EXAMPLE 26 2-Bromo-5-thiomorpholinosulfonylbenzoic Acid This product isprepared by the reaction of 2-bromo' Anal. Calcd for C H O NSBqCKMW461.6):

C, 31.2 Found: C, 31.4

I EXAMPLE 24 2-Chloro-5 3-methoxy-4-hydroxypiperidinosulfonyl benzoicAcid 2-Chloro-5-( 3,4-dihydroxypiperidinosulfonyl )ben- S-chlorosulfonylbenzoic acid with excess thiomorpho- 0 line in methylene chloride. Theproduct, m.p.

l97.5C., is purified by solution in aqueous sodium hydroxide,crystallization by acidifying the basic solution, and recrystallizationfrom acetone-hexane.

Anal. Calcd for C H OJQS Br (MW 366.26): C, c

6.07; H, 3.30; N, 3.82. Found: 6.24; H, 3.49; N, 3.96.

zoic acid (4.0 g.) is heated for 16 hours at 90 C. with water (15 ml.),NaOH (1.0 g.) and dimethyl sulfate2-Bromo-5-thiomorpholinosulfonylbenzoic Acid, 1 -Oxide 24 6N sodiumhydroxide solution. The reaction is extracted rapidly with ethylacetate, and the aqueous layer acidified with 12N hydrochloric acid andex tracted with ether. Removal of the ether from the sepaand cooled. Theresulting crystalline product, 1.5 rated organic phase provides g. ofthe crude prodgrams, m.p.' 237-239 C., is recovered by filtration, uct,m.p. 119-125 C. The product is recrystallized washed with acetic acidand methnol. from benzene-hexane, 7.6 g., m.p. 131132 C.

Anal. Calc'd for c,,11,,o,Ns,BR (MW 382.26): c. 34.56; H. 3.16; N. 3.66.Found: c. 34.59; H. 3.20; N. 3.46.

EXAMPLE 27 2-Chloro-5-(3,5-dimethylpiperidinosulfonyl)benzoyl figfifgfg; 2125,; 31;}; ,1; if?) chloride2-Chloro-5-(3,5-dimethy1piperidinosulfonyl)benzoic acid (6.0 g.) isrefluxed for 2 /2 hours with 50 ml. of thi- Stamps with the pp p areagents a repeating onyl chloride, and then taken to dryness. Theresidue the general procedurabovei the follpwmg congners is trituratedwith 200 ml. of hot benzene-hexane (1:1 l syntheslzedi lgy filtered andevaporated to obtain the dry product, m.p. methylamin 9 Y acldi P-P' 6 6C and 2-methylthio-5-sulfamylbenzo1c ac1d, m.p. v I hl 5 3 5 d' th 1 'd'osulfonyl) 278L2790C1 N- 2-c oro- ClS- 1me yp1per1 1n I benzoy11g1ycineEXAMPLE 30 2-Chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)- h P benzoylchloride (2.4 g.) and glycine (525 mg.) are dislammosulfonynbenzolcsolved in ml. of water, 30 ml. of acetone and 14 ml. a.2-ch1oro-5-(2-p-chlorophenethylaminosulfonyl)b of 1N sodium hydroxide.After stirring at room temperzoic a id attire for about 25 minutes, thereaction mixture is To a. solution of 45 g. (0.29 mole) of 2-pacidifiedwith concentrated hydrochloric acid. The pre- 30 chlorophenethylamine in200 ml. of methylene chlocipitated material is recrystallized fromacetone (25 ride is added, portionwise over a 15 minute period,ml.)-hexane ml.) to yield the product, m.p. 25.5 g. (0.1 mole)of2-chloro-5-chlorosulfony1benzoic 189l9l .5 1 acid. additional 150 ml. ofsolvent is added, and the Anal. Calcd for C,,H,.0,N,SC1 (MW 388.9): c,49.41; H, 5.44; N, 7.20

Found: C, 49.55; H, 5.43; N, 7.

EXAMPLE 28 N-[ 2-Chloro-5-(cis-3,5-

dimethylpiperidinosulfonyl)benzoy1]-4-aminobutyric Acid,

. 5O cipitate is dissolved in '50 ml. of hot acetone-methanol (1:1) andconcentrated to half volume. Hexane is added to crystallize the product,m.p. l93l95 C.

mixture is allowed to stir overnight at room tempera- 4O ture. Thefiltered crude product is dissolved in 1N sodium hydroxide, extractedwith ether, and the aqueous layer separated and acidified with 12Nhydrochloric acid. The resulting product is filtered and dried, 31 g.m.p. l-l77 C.

Anal. Calcd for c, ,H, ,o,Nsc1,; c. 48.14; 11. 3.50; N. 3.72. Found: c.48.19; 11. 3.31; N. 3.42.

b. 2-chloro-5-(N-ethy1-N-[2-p-chlorophenethyl- ]aminosulfonyl)benzoicAcid To a refluxing solution of 3.74 g. (0.01 mole) of the Anal. Calc'dfor C H O N SCI (MW 416.9): C. 51.85; H,

Found: C. 51.43; H,

I EXAMPLE 29 Z-Methylthio-5-di-n-butylaminosulfonylbenzoic Acid To asolution containing 11.7 g. (0.03 mole) of 2-'bromo-5-di-n-butylaminosulfonylbenzoic acid and 3.6 g. (0.066 mole) ofsodium methoxide is added through a gas dispersion tube 4.5 g. (0.1mole) of methylmercaptan, and the reaction mixture heated under nitrogenat 1 10 C. for 19 hours. The reaction is cooled. diluted withml. ofwaterand made strongly basic with a .60 above intermediate in 30ml. ofethanol is gradually sodium sulfate and concentrated in vacuo. Theresidual oil on trituration with hexane solidifies, 3.6 g., m.p. 128-130C. Recrystallization from chloroformhexane provides the purifiedproduct, m.p. 129130 C.

Anal. Calcd for C H NO SCl C. 50.76; H, 4.26; H 4.26;

N, 3.48. Found: C, 50.31; N, 3.48.

Starting with 2-chloro-5-(2-p-chlorophenethylaminosulfonyl)benzoic acidand the appropriate halide, and repeating the above alkylationprocedure, the following analogs are prepared: 2-chloro-5-(N- benzyl-N-[2-p-chlorophenethyl]aminosulfonyl)benzoic acid, mp. 140-142 C.,2schloro-5-(N-methyl-N- [2-p-ch1orophenethy1laminosulfonyl)benzoic acid,m.p. l26128 C.;2-chloro-5-(N-n-propyl-N-[2-pchlorophenethyl]aminosulfony1)benzoic acid,m.p.

137l39C. and 2-chloro-5(N-p-phenylbenzyl-N-[2-p-chlorophenethyl]aminosulfonyl)benzoic acid, mp. 181182.5 C.

EXAMPLE 31 2,3-Dichloro--(cis-3,S-dimethylpiperidinosulfonyl)- benzoicAcid To 5.3 g. (45.5 m moles) of chlorosulfonic acid is addedportionwise over a period of 5 min. 1.0 g. (5.2 m moles) of commerciallyavailable 2,3- dichlorobenzoic acid, and the mixture heated to 155 C.for 2 hrs. The reaction is cooled, poured into 100 g. of ice and theprecipitated solid filtered, 1.03 g., m.p.

135145 C. Sublimation at 163 C. gave 819 mg.,

of 2,3-dichloro-5- H. 4.69; N, 3.84. Found: C, 46.13; H, 4.70; N, 3.76

EXAMPLE 32 The procedure of Example 31 is repeated, starting with2,3-dichlorobenzoic acid and the requisite amine to provide thefollowing compounds:

2,3-dichloro-5-piperidinosulfonylbenzoic acid, m.p. 193-194 C.;

2.3-dichloro-5-di-n-butylaminosulfonylbenzoic acid,

m.p. 161162 C.; and

and 2,3-dichloro-5-(2-p-chlorophenethylaminosulfonyl)benzoic acid, m.p.l57158.5 C.

EXAMPLE 33 2,3-Dichloro 5-(N-ethyl-N-[2-p-chlorophenethyl1-aminosulfonyUbenzoic Acid bromo-5-di-n-propylaminosulfonylbenzoic ln amanner similar to that in Example 30b, 2.0 g. (4.9 m moles) of2,3-dichloro-5-(2-p-chlorophene thylaminosulfonyl)benzoic acid isalkylated with 2.32 g. (15 m moles) of ethyl iodide in 20ml. of ethanolcontaining 15ml. of 1N sodium hydroxide solution. The crude product wasrecrystallized from chloroform, 1.04 g., m.p. 142l44 C.

Anal. Calcd for C H O NSC1 C. 46.75; H, 3.66; N. 3

Found: C. 46.77; H. 3.6l; N. 3.

EXAMPLE 34 Starting with the appropriate 2,3-disubstituted benzoic acidand requisite amine, the procedure of Example 31 is repeated, providingthe following compounds;

2,3-difluoro-5-(cis-3,5-dimethylpiperidinosulfonyl)- benzoic acid;2,3-difiuoro-5-(2-p-chlorophenethylaminosulfonyl)benzoic acid;2,3-difiuoro-5-morpholinosulfonylbenzoic acid;2,3-dibromo-5-dimethylaminosulfonylbenzoic acid; 2-bromo-3-ch1oro-5-hexamethyleneiminosulfonylbenzoic acid; 2-chloro-3- acid; 2chloro-3-bromo-5-(3,4-dichlorobenzylaminosulfonyl)- benzoic acid;2-methy1-3-fluoro-5-(4-methylpiperidinosulfonyl)benzoic acid; 2-methy1-3-fluoro-5- di-n-propylaminosulfonylbenzoic acid; 2-methyl-3-fluoro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoic acid;2-methyl-3-fiuoro-5-(2-p-chlorophenethylaminosulfonyl)benzoic acid;2-chloro3-methyl-5- (cis-3,5-dimethylpiperidinosulfonyl)benzoic acid; 2-

chloro-3-methyl-5-(2-p-chlorophenethylaminosul- EXAMPLE 352,4Dichloro-5-piperidinosulfonylbenzoic Acid A stirred suspension of 1.7g. (0.02 mole) of piperidine and 5.8 g. (0.02 mole) of 2,4-dich1oro-5-chlorosulfonylbenzoic acid (Sturm, et al., Ber., 99, 328 (1966) in m1.of water and cooled to 15 C. is treated dropwise with 50 ml. of 1Nsodium hydroxide. When the addition is complete, the: mixture is allowedto warm to room temperature and remain for 1 hr. The hazy suspension isfiltered and the clear filtrate acidified with 12N hydrochloric acid.The precipitated solids are filtered and dried, 7.7 g., m.p. 200-205 C.A sample is recrystallized from acetonitrile, m.p.

Anal. Calcd for C H O NSCE: C, 42.62; H,

3 87; N, Found: C, 42.35; H, 3.77 N

EXAMPLE 36 benzoic acid, m.p. l92194 C. v

- EXAMPLE 37 2,4-Dichloro --(N-ethyl-N-[2-p-chlorophenethyl]-aminosulfony1)benzoic Acid The procedure of Example (b) is againrepeated, starting with 2.5 g. (6 m moles) of2,4-dic'hloro-5-(2-pchlorophenethylaminosulfonyl)benzoic acid and 3.12g. (0.02 mole) of ethyl iodide to give 1.74 g. of the desired product,m.p. 132l34 C.

EXAMPLE 38 Starting with the requisite 2,4-disubstituted benzoic acid,chlorosulfonic acid and the appropriate amine,

' the procedure of Example 31 is repeated to provide the followingcongeners:

' 2,4-dichloro-5-dimethylaminosulfonylbenzoic' acid;2,4-dichloro-5-(4,4-dimethylpiperidinosulfonyl)benzoic acid;2,4-difluoro-5-(3-p-bromophenylpropylaminosulfonyl)benzoic acid;2,4-difluoro-5-morpholinosulfonylbenzoic acid; 2-fluoro-4-chloro-5-(3-chlorophenylaminosulfonyl)benzoic acid; 2-fluoro-4-chloro-S-hexamethyleneiminosulfonylbenzoic acid; 2-

chloro-4-fluoro 5-(2,4-dimethylpiperidinosulfonyl)- benzoic acid;2-ch1oro-4-fluoro-5-(2-p-methylphenethylaminosulfonyl)benzoic acid;2,4-dibromo-5-(cis- 3 ,5-dimethylpiperidinosulfonyl)benzoic acid; 2,4-dibromo-S-diethylaminosulfonylbenzoic acid; 2,4-dibromo-S-phenylaminosulfonylbenzoic acid; 2-

phenylaminosulfonylbenzoic acid; and 2-methyl-4-methoxy-S-hexamethyleneiminosulfonylbenzoic acid.

EXAMPLE 39 2,6-Dichl0ro-5-piperidinosulfonylbenzoic Acid a. To a stirredsolution of chlorosulfonic acid (10.6 g.;'0.09 mole) is added 1.91 g.(0.01 mole) of commercially available 2,6-dichlorobenzoic acid and theresulting reaction solution heated to 155 C. for min. The solution iscooled, poured into ml. of ice-water and the resulting white precipitatefiltered and dried, 1.8 g., m.pl -160 C. Recrystallization fromchloroform gave 1.2 g. of 2,6-dichloro-5-chlorosulfonylbenzoic acid,m.p. 171 C.

Anal. Calcd for C,H ;O Sl;,S: C, 29.04; H, 1.04. Found: C, 29.30; H,1.05.

b. 2,6-Dich1oro-5-chlorosulfonylbenzoic acid (960 mg.; 3.3 m moles) isadded portion-wise to 1.95 g. (0.0165 mole) of piperidine in 15 ml. ofdry methylene chloride, and the mixture heated to reflux for 1.5 hrs.The solvent and excess amine are removed under reduced pressure and theresidue dissolved in 15 ml. of 2N sodium hydroxide. The aqueous basesolution is extracted (2 X 50 ml.) with ether and acidified with 6Nhydrochloric acid. The precipitated gum is filtered, dried and allowedto crystallize in hexane, 1.1 g., m.p. l45l 50 C. A small sample isrecrystallized from acetonitrile, m.p. l42-145 C.

Anal. Calc'd for C, H, O,NSCI;: C, 42.62; H, 3.87; N, 4.1

Found: C, 42.56; H, 4.00; N, 4.1..

- EXAMPLE 40 EXAMPLE 41 1 Starting with 350mg. of2,6-dichloro-5-(2-pchlorophenethylaminosulfonyl)benzoic acid and 1 ml.of ethyl iodide and following the procedure of Example 30(b),2,6-dichloro-5-(N-ethyl-N-[2-pchlorophenethyl]aminosulfonyl)-benzoicacid is prepared, m.p. l38139 C.

EXAMPLE 42 The procedure of Example 31 is repeated, starting with theappropriate amine, 2,6-disubstituted benzoic acid and chlorosulfonicacid, to provide the following compounds:

2,6-dichloro-5-morpholinosulfonylbenzoic acid; 2,6-dichloro-5-di-n-butylaminosulfonylbenzoic acid; 2,6dichloro-5-(4-bromobenzylaminosulfonyl)-benz0ic acid;2-fluoro-6-chl0ro-5-piperidinosulfonylbenzoic acid;2-fluoro-6-chloro-5-hexamethyleneiminosulfonylbenzoic acid;2-fluoro-6-chloro-5-dimethylaminosulfonylbenzoic acid;2,6-difluoro-5-(3,4- dichlorophenylaminosulfonyl)-benzoic acid; 2,6-difluoro-S-morpholinosulfonylbenzoic acid; 2,6-difluoro-S-(4,4-dimethylpiperidinosulfonyl)benzoic acid;2,6-difluoro-5-(3,5-dimethylpiperidinosulfonyl)- and EXAMPLE 434-Chloro-5-di-n-butylsulfamylbenzoic Acid To a solution of 3.9 g'. (0.03mole) of di-n-butylamine in ml. of methylene chloride is added 2.5 g.(0.01 mole) of 4-chloro-5-chlorosulfonylbenzoic acid (J.Pharm.'Pharmacol., 683 (1962), and the resulting reaction mixtureallowed to. stir at room temperature for 3 hrs. The solvent is removedunder reduced pressure and the residue partitioned between 1N sodiumhydroxide and diethyl ether. The aqueousphase is sepa- Anal. ctncu for CH CLNSCI: c. 49.13; H. 5.044; N. 4.41. Found: C. 49.42; H. 5.13; N.4.35.

EXAMPLE 46 3-Chloro--5-(3,S-dimethylpiperidinosulfonyl)benzoic Acid 43-Chloro-5-chlorosulfonylbenzoic acid (770 mg., 3 m moles) is added to asolution of 3,5 dimethylpiperidine hydrochloride in 30 ml. of waterfollowing by the portionwise addition of 12 ml. of IN sodium hydroxidesolution with stirring. After 1.5 hrs. at room temperature the reactionmixture is filtered and the filtrate acidified with 12N hydrochloricacid.

The product, 600 mg., mp. 22623l C., is recrystallized fromacetone-hexane, 390 mg., mp. 232.5-234 C.

' Anal. Calcd for c a omscu c. 50.67; H. 5.47; N. 4.22.

Found: C. 50.43; H, 5.40; N, 4.07.

rated, acidified with l2N hydrochloric acid and the precipitated solidfiltered and dried, 3.0 g., m.p.

93-96 C. Recrystallization from ether-hexane provides the pure product,2.5 g., m.p. 94.596.5'C.'

8.61.4.3. Found: C, 5l.86; H. 6.37; N, 3.79.

EXAMPLE 44 Starting with the appropriate 4-s ubstituted benzoic I acidand requisite amine, the procedureof Example 30 is repeated to providethe following compounds:

4-fluoro-5-dimethylaminosulfonylben zoic acid; 4-fluoro-S-piperidinosulfonylbenzoic acid; -4-chloro-5-(3,5-dimethylpiperidinosulfonyl)benzoic acid; 4-chloro-5-morpholinosulfonylbenzoic acid; 4-chloro-5-(3-methylpiperidinosulfonyl)benzoic acid; 4-bromo-5-hexamethyleneiminosulfonylbenzoic acid; 4-bromo-5-(4-chlorobenzylaminosulfonyl)benzoic acid; 4-methyl-5-(4,4-dimethylpiperidinosulfonyl)benzoic acid; 4-methyl-5-(3,5-dibromophenylaminosulfonyl)-benzoic acid;4-methyl-5-(3-phenylpropylaminosulfonyl)benzoic acid;4-methoxy-5-(2,4-dimethylpiperidinosulfonyl)benzoic acid;4-methoxy-5-(4-biphenylethylaminosulfony])benzoic acid;4-methoxy-5-(2-pbromophenethylaminosulfonyl)-benzoic acid; and 4-methoxy-S-di-i-propylaminosulfonylbenzoic acid.

EXAMPLE 3-Chloro-5-(3-methylpiperidinosulfonyl)benzoic acid Theprocedure of Example 43 is repeated, starting with 5 g. (0.05 mole) of3-methylpiperidine and 2.5 g. (0.01 mole) of3-chloro-5-chlorosulfonylbenzoic acid in 15 ml. of methylenechloride,providing 2.7 g., m.p. l77-l79C. of the crude product.Purification is effected by recrystallization from acetone-hexane, 1.2g., m.p. l8l-l83 C.

EXAMPLE 47 3-Trifluoromethyl-5-(3-methylpiperidinosulfonyl)benzoic AcidThe procedure of Example 43 is repeated, starting with 2.g. (0.02 mole)of 3-methylpiperidine in 10 ml. of methylene chloride and 1.8 g. (6.3 mmoles) of 3- trifluoromethy[-5-chlorosulfonylbenzoic acid to give, afterrecrystallization from acetone-hexane, 1.3 g., m.p. 206-207.C. of thedesired product.

Anal. Calcd for C' H QNSF C, 47.86 7 82 Found: C, 4 ;H,

EXAMPLE 48 Reaction of .the appropriately 3-substituted-5-chlorosulfonylbenzoic acid, prepared by chlorosulfonation of thecorresponding benzoic acid, with the requisite amine employing theprocedure of Example 43 leads to the preparation of the followingcompounds:

3-fluoro-S-hexamethyleneiminosulfonylbenzoic acid;3-fluoro-5-di-i-butylaminosulfonylbenzoic acid; 3-fluoro-5-(3,4-dimethylbenzylaminosulfonyl)-benzoic acid;3-bromo-5-morpholinosulfonylbenzoic acid; 3- bromo-5-( 3,5-dimethylpiperidinosulfonyl )benzoic acid;3-bromo-5-diethylaminosulfonylbenzoic acid; 3-methyl-S-piperidinosulfonylbenzoic acid; 3-methyl-5-(4-bromophenylaminosulfonyl)-benzoic acid; 3-methyl-5-(2-p-tolylethylaminosulfonyl)benzoic acid;3-methoxy-5-(2,3-dimethylpiperidinosulfonyl)benzoic acid; v3-methoxy-5-di-i-propylaminosulfonylbenzoic acid;3-methoxy-5-hexamethylerieiminosulfonylbenzoic acid;3-chloro-5-(2-p-chlorophenethylaminosulfo'nyl )benzoic acid;3-trifl'uoromethyl-5-( 3 -pbromophenylpropylaminosulfonyl)benzoic acid;3-

-- trifluoromethyl-5-(3,S-dimethylpiperidinosulfonyl)- benzoic acid; andbutylaminosulfonylbenzoic acid.

v EXAMPLE 49 5-(cis-3,5-dimethylpiperidinosulfonyl -6- chlorobenzoicAcid 'with chloroform (2 X .300 ml.). The organic layer is separated,dried over magnesium sulfate and concentratedto give an oil 11.6 g. Asolution of the residual oil in diethyl etheris converted to thehydrochloride salt at C. using hydrogen chloride gas. The intermediate,methyl 3-ami'no-2-chlorobenzoate hydrochloride is filtered and airdried, 15.9 g., m.p. 188.5l90 C.

A mixture of 15.6 g. (70 m moles of 3-amino-2- chlorobenzoatehydrochloride, 70 ml.- of acetic acid and Y12 ml. of 12N hydrochloricacid is stirred at 10 C. while a solution of sodium nitrite (5.35 g., 77m moles) in 7 ml. of water is added over a min. period. After stirringat C. for 30 min., sulfur dioxide (42 g., 660 m moles) in 98 ml. ofacetic acid containing 704 mg. of cuprous chloride is added, and thegreen reaction mixture allowed to stir at 10 C. for 1.5 hrs. Water (140ml.) .is then added and the solution is extracted with methylenechloride (3 X 100 ml.). The combined extracts are washed withcold brinesolution and dried over magnesium sulfate. Concentration of the organicsolution provides 19.6 g. of the crude methyl 2-chloro-3-chlorosulfonylbenzoate.

To a solution of potassium carbonate (24 g., 174 m moles) andcis-3,S-dimethylpiperidine hydrochloride (15.9 g., 105 m moles) in 140ml. of water is added 18.9 g. of methyl2-chloro-3-chlorosulfonylbenzoate in 350 ml. of benzene, and the mixtureallowed to stir at room temperature for-l hr. The organic layer isseparated, dried over magnesium sulfate and concentrated to an oil whichcrystallizes on standing. The solid intermediate methyl 5-(cis-3,5-dimethylpiperidinosulfonyl)-6-chlorobenzoate is triturated with hexaneand filtered, 19.8 g., m.p. 92.593.5 C.

An aqueous solution of 4.2 g. (105 m moles) of sodium hydroxide in 130ml. of water is added to 18 g.

(52.5 m moles) of methyl 5-(cis-3,5-dimethylpiperidinosulfonyl)-6-ch1orobenzoate in 130 325-hexamethyleneiminosulfonyl-6 fluorobenzoic acid;5-piperidinosulfonyl-6-fiuorobenzoic acid;5-di-npropylaminosulfonyl-6-fluorobenzoic acid;5-(2-pbromophenethylaminosulfonyl)'-6-fluorobenzoic acid;

5-phenylaminosulfonyl-6-bromobenzoic acid; 5-(cis-5-morpholinosulfonyl-6-methylbenzoic acid.

EXAMPLE 51 phenylaminosulfonyl)benzoic acid; 2-bromo-4-methylml. ofmethanol, and resulting reaction mixture allowed 4 to stir at 40 C. for1 hr. The solution is poured into ice water 1.51.) and extracted severaltimes with benzene.

The aqueous phase is separated, acidified with 12Nhydrochloric acid, andthe precipitated product filtered and air dried, 17.3 g.Recrystallization from ethyl acetatehexane gave the purified product,16.4 g., m.p. 152.5-153 C.

I EXAMPLE 50 chlorophenethylaminosulfonyl)-6-chlorobenzoic acid;

5-(N-n-butyl-N-[2-p-chlorophenethyl]aminosulfonyl)- benzoic acid;2-chloro-4-methoxy-5-(N-methyl-N-[3- Z-methyl-4-chlorophenylpropyl]aminosulfonyl)benzoic acid; 2-fluoro-4-methyl-5-(N-n-propyl-N-phenylaminosulfonyl)benzoic acid; 2,6-dichloro-5-(N- i-butyl-N-[4-bromobenzyl]aminosulfonyl)benzoic acid;2,6-difluoro-5-(N-n-butyl-N-[3,4-dichlorophenyl- ]aminosulfonyl)benzoicacid; 2-chloro-6-methyl-5-(N- ethyl-N-4-tolylaminosulfonyl)benzoic acid;2-chloro-6- methyl-5-(N-methyl-N-[3- 4-bromophenylpropyl-]aminosulfonyl)benzoic acid; 2-methyl-6-bromo-5-(N-n-propyl-N-4-tolylaminosulfonyl)benzoic acid; 2- bromo-6-methyl-5-(N-ethyl-N-4- tolylaminosulfonyl)benzoic acid;2,6-dimethyl-5-(N- methyl-N-4-biphenylaminosulfonyl)benzoic acid; 4-bromo-5-(N-methyl-N-[4-bromobenzyl]aminosulfonyl)benzoic acid;4-methyl-5-(N-i-buty1-N-[3,5- dibromophenyl ]aminosulfonyl )benzoicacid; 4- methoxy-5-(N-ethyl-N-4- biphenylaminosulfonyl)benzoic acid;3-methyl-5-(N- ethyl-N-4-bromophenylaminosulfonyl)benzoic acid;3-methyl-5-(N-ethyl-N-[2-p-tolylethyl]aminosulfonyl)- benzoic acid;3-chloro-5-(N-ethyl-N-[2-pchlorophenethyl ]aminosulfonyl )benzoic acid;3- trifluoro-5-( N-methyl-N-[ 3-p-bromophenylpropyl-]aminosulfonyl)benzoic acid;S-(N-ethyl-N-[Z-pchlorophenethyl]aminosulfonyl)-6-chlorobenzoic acid;5-( N-i-propyl-N-phenylaminosulfonyl )-6- bromobenzoic acid;S-(N-ethyl-N-[Z-pacid; and

, v 3 chlorophenethyl]aminosulfonyl)-6-methylbenzoic2-fluoro-5-(N-methyl-N- phenylaminosulfonyl)benzoic acid.

EXAMPLE 52 The procedure of Example 15 is repeated, starting with therequisite amine and 2-fluoro-5- sulfamylbenzoic acid, to give thefollowing congenerszZ-diethylamino-3-fluoro-5-(cis-3,5-dimethylpiperidinosulfonyl)benzoicacid; 2-piperidino-3-fluoro- 5-(cis-3,5-dimethylpiperidinosulfonyl)benzoic acid; 2-piperidino-3fluoro-5-morpholinosulfonylbenzoic acid; 2-hexamethyleneimino-3-fluoro-5-morpholinosulfonylbenzoic acid; 2-di-nbutylamino-3- chloro-5-(cis-3,5-dimethylpiperidinosulfonyl)benz'oicacid; 2-piperidino-3-chloro-5-diethylaminosulfonylbenzoic acid;2-piperidino-3-methyl-5- phenylaminosulfonylbenzoic, acid; 2-hexamethyleneimino-3-chloro-5- piperidinosulfonylbenzoic acid;Z-(N-ethyl-N-npropylamino)-3-trifluoromethyl-5-(cis-3;5-dimethylpiperidinosulfonyl)benzoic acid; 2-diethylamino-4-fluoro-5-(3-p-bromophenylpropylaminosulfon'yl)ben- EXAMPLE 53 Theprocedure of Example 18 is repeated, starting 2-methoxy-3-methyl-5- 342-methoxy-4-chloro-5-hexamethyleneiminosulfonylbenzoic acid;2-methoxy-4-methyl-5- piperidinosulfonylbenzoic acid;2-methoiry-4-methyl-5- phenylaminosulfonylbenzoic acid; 2,4-dimethoxy 5-hexamethyleneiminosulfonylbenzoic acid; Z-methoxy-6-fluoro-5-(3,4-dichlorophenylaminosuIfonyl)benzoic acid; 2-methoxy-3-fluoro-5-(N-ethyl-N-[2-pchlorophenethyl]aminosulfonyl)benzoic acid; 2-methoxy-3'-methyl-5-(N-methyl-N phenylaminosulfonyl)benzoic acid; and2-methoxy-4- methyl-5-('N-n-propyl-N-phenylaminosulfonyl)benzoic acid.

] EXAMPLE 54 A dry solid pharmaceutical composition isprepared byblending the followingmaterials together in the specified weightproportions:

2-chloro-5-(cis 3.S-dimethylpiperidinosulfonyl)- 50 benzoic acid sodiumcitrate 25 alginic acid polyvinylpyrrolidone I0 magnesium stearate Afterthe dried composition is thoroughly blended, tablets are punched fromthe mixture, each tablet being of such size as to contain 100 mg. of theactive ingredient. Tablets are also prepared containing, respectively,5, 10, and mg. of the active ingredient, by employing the appropriateproportions of 2-chloro-5-(cis- 3,5-dimethylpiperidinosulfonyl)benzoicacid and excipient blend in each case.

EXAMPLE 55 A dry solid pharmaceutical composition is prepared bycombining the following materials in the indicated weight proportions:

2-chloro-5-tcis-3,S-dimetliylpiperidinosu|f0nyl) 50 benzoic acid 7calcium carbonate 20 polyethylene glycol. average molecular weight 400030 The dry mixture is thoroughly agitated to obtain a completely uniformblend. Soft elastic and hard gelatin capsules containing thiscomposition are then prepared, employing sufficient material to provideeach capsule with 190 mg. of active ingredient.

EXAMPLE 56 Groups, each comprising four animals, of normalSprague-Dawley (Charles River) male rats weighing from to 220 grams arefed rat chow containing the test compounds for two overnight feedingperiods. On the morning of the third day the animals are anesthetizedandbled from the abdominal aorta. The total plasma cholesterol is thendetermined by the method of J. J. Carr and l. .I. Drekter reported inCliri. Chem, 2, 353 (1956). Most of the tests are conducted at aconcentration in the feed of 0.15 to 0.25 weight percent of the compoundunder test, but lower levels are employed in some instances. The totalquantity of test compound consumed is computed from feed consumptionover the two-day period and is tabulated, in milligrams per kilogrambody weight per day, along with the associated percent cholesterol fallmeasured:

Daily Cholesterol Dosage Compound Fall mg./kg.

2-chloro-5-( trans-dl-3 benzoic acid

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULA2. A compound selected from the group consisting of those of the formula3. A compound selected from the group consisting of those of the formula4. A compound selected from the group consisting of those of the formula5. A compound selected from the group consisting of those of the formula6. A compound selected from the group consisting of those of the formula7. A compound selected from the group consisting of those of the formula8. A compound selected from the group consisting of those of the formula9. A compound selected from the group consisting of those of the formula10. A compound selected from the group consisting of those of theformula
 11. A compound selected from the group consisting of those ofthe formula
 12. A compound selected from the group consisting of thoseof the formula
 13. The compound of claim 12 wherein Z is chloro.
 14. Thecompound of claim 12 wherein Z is bromo.